BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by the progressive loss of motor function, leading to paralysis and death. Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA]), a free radical scavenger, was US Food and Drug Administration-approved for ALS treatment in 2017. In preclinical studies, edaravone reduced phenotypes in mouse models with a SOD1 mutation and in SOD1 mutation carrier-derived induced pluripotent stem cells (iPSCs). Despite these findings, the broader applicability of edaravone in ALS treatment, particularly for non-SOD1 mutations which comprise the vast majority of sporadic ALS cases, remains poorly understood.
OBJECTIVES: Considering the aggregation of TARDBP (TDP-43) protein is observed in over 97% of ALS cases, we aimed to examine the effect of edaravone on spinal motor neurons derived from an ALS patient harboring a TDP-43 mutation.
RESULTS: iPSCs of an ALS patient carrying the A382T mutation in TDP-43 were differentiated into spinal cholinergic neurons. These cells were treated with 30 µM edaravone for intervals of 6, 12, and 24 hours after one week of culture. We then performed a neuronal cell death assay, immunocytochemistry, and RNA sequencing to assess the effects of treatment. Edaravone showed neuroprotective effects on iPSC-derived motor neurons from an ALS patient with the TDP-43 mutation. In addition, edaravone corrected the mislocalization of TDP-43 in these cells. A comprehensive transcriptomic analysis indicated significant upregulation and downregulation of over 1000 differentially expressed genes (DEGs) in the edaravone-treated neurons, surpassing the effects seen with vitamin C, another antioxidant, under similar conditions. Gene ontology and pathway analyses of these DEGs underscored their association with processes and pathways crucial for neuronal survival, protein homeostasis, and stress resilience. These findings suggest edaravone operates through a unique mechanism distinct from other antioxidants in ALS.
CONCLUSION: Our findings provide evidence suggestive of the capacity of edaravone to induce transcriptomic changes leading to neuroprotection in ALS models, particularly those involving TDP-43 pathology. Our iPSC data from the A382T mutation in a TDP-43 ALS case support the therapeutic value of edaravone in ALS and opens new avenues for the development of treatment strategies aimed at modulating TDP-43-related pathways.